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High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin


In thalassemia, deficient globin-chain production during erythropoiesis results in anemia1,2,3. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death4. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism5. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 ± 50 pg/ml. In comparison, individuals with β-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 ± 9,600 pg/ml; range 4,800–248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.

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Figure 1: Transcriptional profiling of TGFB superfamily members during erythropoiesis.
Figure 2: GDF15 concentration in human blood and correlation with concentrations of hemoglobin, erythropoietin, soluble transferrin receptor and ferritin in blood from thalassemia patients.
Figure 3: Regulation of hepcidin mRNA expression by GDF15.
Figure 4

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The National Institutes of Health Department of Transfusion Medicine, National Institute of Diabetes and Digestive and Kidney Diseases Microarray Core Laboratory, and S. Strom, J. Goodnough, G. Moser and M. Ehinger performed or assisted with studies involving hepatocytes and transgenic mice. We thank C. Deng, C. Philpott, and A. Schechter for critical reading of the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

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Authors and Affiliations



T. T., manuscript writing, performed experiments, assembly of data. N.V.B., collection and assembly of array data. P.A.O., collection of clinical samples and data. S.-H.G., provision of study material, array data analysis. P.S., collection of clinical samples and data. Y.T.L., collection and assembly of array data. J.W.M., collection of clinical samples. C.H.R., collection of clinical samples and data. N.L.C.L., collection of clinical samples and data. R.-H.W., expertise with hepatic iron assessment. T.E., expertise with GDF15 transgenic mouse. R.C., collection of clinical samples and data. T.G., mouse GDF15 analyses, manuscript revision. S.F.L., collection of clinical samples and data. S.F., collection of clinical samples and data. J.L.M., manuscript writing, experimental conception and design, assisted and supervised research team.

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Correspondence to Jeffery L Miller.

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A provisional patent (Application No. 601864.705) was generated on the basis of these findings.

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Tanno, T., Bhanu, N., Oneal, P. et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13, 1096–1101 (2007).

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